Early everolimus-facilitated reduced tacrolimus in liver transplantation: Results from the randomized HEPHAISTOS trial.

Background Everolimus-facilitated reduced tacrolimus exposure (EVR+rTAC) at 30 days post-liver transplantation (LT) has shown advantages in renal preservation. This study evaluated the effects of early initiation of EVR+rTAC in de novo liver transplant recipients (LTR). Methods In HEPHAISTOS (NCT01551212, EudraCT 2011-003118-17), a 12-month (M), multicenter, controlled study, LTR were randomized at 7-21 days post-LT to receive EVR+rTAC or standard tacrolimus (sTAC), with steroids. The primary objective was to demonstrate superior renal function (assessed by estimated glomerular filtration rate [eGFR]) with EVR+rTAC versus sTAC at M12 in full analysis set (FAS). Other assessments at M12 included evaluation of renal function in compliance set and on-treatment (OT) patients, efficacy (composite endpoint of graft loss, death or treated biopsy proven acute rejection [tBPAR] and individual components) in FAS, and safety. Results In total, 333 patients (EVR+rTAC: 169, sTAC: 164) were included in the FAS. A high proportion of patients was non-adherent in maintaining tacrolimus trough levels (EVR+rTAC: 36.1%, sTAC: 34.7%). At M12, the adjusted LS mean eGFR was numerically higher with EVR+rTAC versus sTAC (76.2 vs 72.1 mL/min/1.73 m2 , difference: 4.1 mL/min/1.73 m2 , P=0.097). A significant difference of 8.3 mL/min/1.73 m2 (P=0.03) favoring EVR+rTAC was noted in the compliance set. Incidence of composite efficacy endpoint (7.7% vs 7.9%) and tBPAR (7.1% vs 5.5%) at M12, as well as incidence of treatment emergent adverse events (AEs) and serious AEs were comparable between groups. A lower proportion of patients discontinued EVR+rTAC than sTAC treatment (27.2% vs 34.1%). Conclusion Early use of EVR in combination with rTAC showed comparable efficacy, safety, and well-preserved renal function versus sTAC therapy at M12. Of note, renal function was significantly enhanced in compliance set.